scholarly journals A zebrafish screen reveals Renin-angiotensin system inhibitors as neuroprotective via mitochondrial restoration in dopamine neurons

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Gha-Hyun J Kim ◽  
Han Mo ◽  
Harrison Liu ◽  
Zhihao Wu ◽  
Steven Chen ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Neuroprotective Effect ◽  
Disease Model ◽  
Renin Angiotensin System ◽  
Dopamine Neurons ◽  
Renin Angiotensin ◽  
Pathway Gene ◽  
Raas Inhibitors

Parkinson’s disease (PD) is a common neurodegenerative disorder without effective disease-modifying therapeutics. Here, we establish a chemogenetic dopamine (DA) neuron ablation model in larval zebrafish with mitochondrial dysfunction and robustness suitable for high-content screening. We use this system to conduct an in vivo DA neuron imaging-based chemical screen and identify the Renin-Angiotensin-Aldosterone System (RAAS) inhibitors as significantly neuroprotective. Knockdown of the angiotensin receptor 1 (agtr1) in DA neurons reveals a cell-autonomous mechanism of neuroprotection. DA neuron-specific RNA-seq identifies mitochondrial pathway gene expression that is significantly restored by RAAS inhibitor treatment. The neuroprotective effect of RAAS inhibitors is further observed in a zebrafish Gaucher disease model and Drosophila pink1-deficient PD model. Finally, examination of clinical data reveals a significant effect of RAAS inhibitors in delaying PD progression. Our findings reveal the therapeutic potential and mechanisms of targeting the RAAS pathway for neuroprotection and demonstrate a salient approach that bridges basic science to translational medicine.

Therapeutic potential of renin angiotensin system inhibitors in cancer cells metastasis

2020 ◽  
Vol 216 (7) ◽  
pp. 153010 ◽  
Author(s):  
Milad Hashemzehi ◽  
Farimah Beheshti ◽  
Seyed Mahdi Hassanian ◽  
Gordon A. Ferns ◽  
Majid Khazaei ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Therapeutic Potential ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Renin Angiotensin

Androgens augment proximal tubule transport

2004 ◽  
Vol 287 (3) ◽  
pp. F452-F459 ◽  
Author(s):  
Albert Quan ◽  
Sumana Chakravarty ◽  
Jian-Kang Chen ◽  
Jian-Chun Chen ◽  
Samer Loleh ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Specific Binding ◽  
Extracellular Volume ◽  
Renin Angiotensin System ◽  
Angiotensin Receptors ◽  
Sprague Dawley ◽  
Angiotensin System ◽  
Renin Angiotensin

The proximal tubule contains an autonomous renin-angiotensin system that regulates transport independently of circulating angiotensin II. Androgens are known to increase expression of angiotensinogen, but the effect of androgens on proximal tubule transport is unknown. In this in vivo microperfusion study, we examined the effect of androgens on proximal tubule transport. The volume reabsorptive rate in Sprague-Dawley rats given dihydrotestosterone (DHT) injections was significantly higher than in control rats given vehicle injections (4.57 ± 0.31 vs. 3.31 ± 0.23 nl·min−1·mm−1, P < 0.01). Luminally perfusing with either enalaprilat (10−4 M) to inhibit production of angiotensin II or losartan (10−8 M) to block the angiotensin receptor decreased the proximal tubule volume reabsorptive rate in DHT-treated rats to a significantly greater degree than in control vehicle-injected rats. The renal expression of angiotensinogen was shown to be higher in the DHT-treated animals, using Northern blot analysis. The expression of angiotensin receptors, determined by specific binding of angiotensin II, was not different in the two groups of animals. Brush-border membrane protein abundance of the Na/H exchanger, a membrane transport protein under angiotensin II regulation, was also higher in DHT-treated rats vs. control rats. Rats that received DHT had higher blood pressures than the control rats but had no change in their glomerular filtration rate. In addition, serum angiotensin II levels were lower in DHT-treated vs. control rats. These results suggest that androgens may directly upregulate the proximal tubule renin-angiotensin system, increase the volume reabsorptive rate, and thereby increase extracellular volume and blood pressure and secondarily decrease serum angiotensin II levels.

Effects of Tokishakuyakusan, Keishibukuryogan, Shakuyakukanzoto and Unkeito on Ovarian Endothelin, Renin and Angiotensin II in Pregnant Mare's Serum Gonadotropin-treated Immature Rats

1992 ◽  
Vol 20 (02) ◽  
pp. 175-179 ◽  
Author(s):  
Satoshi Usuki ◽  
Yoshie Usuki ◽  
Junko Tanaka ◽  
Yuko Kawakura
Keyword(s):  
Angiotensin Ii ◽  
Herbal Medicines ◽  
Renin Angiotensin System ◽  
Concomitant Treatment ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Immature Rats ◽  
Serum Gonadotropin ◽  
Peptide System

We have previously proposed the ovarian ERAANPS (endothelin-renin-angiotensin-atrial natriuretic peptide system). The present study was undertaken to examine in vivo the effects of herbal medicines [Tokishakuyakusan (TS), Keishibukuryogan (KB), Shakuyakukanzoto (SK) and Unkeito (UT)] on endothelin-l (ET), renin and angiotensin II (A II) in the ovaries, of immature rats treated with 10 IU PMS for 48 h. ET and all components of renin-angiotensin system (RAS) were found at high levels in the ovary. Concomitant treatment with PMS plus TS, KB, SK or UT, especially TS and UT, tended to decrease the ET levels in ovary, while components of RAS tended to increase. However, ET, renin and A II levels in plasma were not at all affected after treatment with TS, KB, SK or UT. These results suggest that TS, KB, SK or UT may regulate the ovarian ERAANPS.

scholarly journals Peptide TFP5/TP5 derived from Cdk5 activator P35 provides neuroprotection in the MPTP model of Parkinson’s disease

2015 ◽  
Vol 26 (24) ◽  
pp. 4478-4491 ◽  
Author(s):  
BK. Binukumar ◽  
Varsha Shukla ◽  
Niranjana D. Amin ◽  
Philip Grant ◽  
M. Bhaskar ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disorder ◽  
Neuroprotective Effect ◽  
Selective Inhibition ◽  
Motor Dysfunction ◽  
Dopamine Neurons ◽  
Dopamine Depletion ◽  
Neuroprotective Effects

Parkinson’s disease (PD) is a chronic neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra, decreased striatal dopamine levels, and consequent extrapyramidal motor dysfunction. Recent evidence indicates that cyclin-dependent kinase 5 (Cdk5) is inappropriately activated in several neurodegenerative conditions, including PD. To date, strategies to specifically inhibit Cdk5 hyperactivity have not been successful without affecting normal Cdk5 activity. Previously we reported that TFP5 peptide has neuroprotective effects in animal models of Alzheimer’s disease. Here we show that TFP5/TP5 selective inhibition of Cdk5/p25 hyperactivation in vivo and in vitro rescues nigrostriatal dopaminergic neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP/MPP+) in a mouse model of PD. TP5 peptide treatment also blocked dopamine depletion in the striatum and improved gait dysfunction after MPTP administration. The neuroprotective effect of TFP5/TP5 peptide is also associated with marked reduction in neuroinflammation and apoptosis. Here we show selective inhibition of Cdk5/p25 ­hyperactivation by TFP5/TP5 peptide, which identifies the kinase as a potential therapeutic target to reduce neurodegeneration in Parkinson’s disease.

The Role of the Renin–Angiotensin System in the Cancer Stem Cell Niche

2021 ◽  
pp. 002215542110262
Author(s):  
Ethan J. Kilmister ◽  
Swee T. Tan
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Signaling Pathways ◽  
Renin Angiotensin System ◽  
Epidemiological Data ◽  
Malignant Cells ◽  
Angiotensin System ◽  
Renin Angiotensin

Cancer stem cells (CSCs) drive metastasis, treatment resistance, and tumor recurrence. CSCs reside within a niche, an anatomically distinct site within the tumor microenvironment (TME) that consists of malignant and non-malignant cells, including immune cells. The renin–angiotensin system (RAS), a critical regulator of stem cells and key developmental processes, plays a vital role in the TME. Non-malignant cells within the CSC niche and stem cell signaling pathways such as the Wnt, Hedgehog, and Notch pathways influence CSCs. Components of the RAS and cathepsins B and D that constitute bypass loops of the RAS are expressed on CSCs in many cancer types. There is extensive in vitro and in vivo evidence showing that RAS inhibition reduces tumor growth, cell proliferation, invasion, and metastasis. However, there is inconsistent epidemiological data on the effect of RAS inhibitors on cancer incidence and survival outcomes, attributed to different patient characteristics and methodologies used between studies. Further mechanistic studies are warranted to investigate the precise effects of the RAS on CSCs directly and/or the CSC niche. Targeting the RAS, its bypass loops, and convergent signaling pathways participating in the TME and other key stem cell pathways that regulate CSCs may be a novel approach to cancer treatment:

Temperature sensitivity of the renin-angiotensin system in Ambystoma tigrinum

1984 ◽  
Vol 246 (4) ◽  
pp. R510-R515 ◽  
Author(s):  
E. Corwin ◽  
G. M. Malvin ◽  
S. Katz ◽  
R. L. Malvin
Keyword(s):  
Temperature Sensitivity ◽  
Renin Angiotensin System ◽  
Plasma Renin ◽  
Competitive Inhibitor ◽  
Renin Activity ◽  
Ambystoma Tigrinum ◽  
Adrenergic System ◽  
Angiotensin System ◽  
Renin Angiotensin

The presence of a renin-angiotensin system was demonstrated in the poikilotherm Ambystoma tigrinum, commonly called the tiger salamander. Standard radioimmunoassay techniques were employed to measure the intrarenal renin activity (IRA) and the plasma renin activity (PRA) of A. tigrinum kept at either 5 or 20 degrees C. Basal IRA and PRA values were not affected by the temperature at which the animals were maintained. Intraperitoneal injection of the beta-adrenergic agonist isoproterenol, however, increased PRA only in those animals maintained at 20 degrees C. This is consistent with the hypothesis of a temperature sensitivity of the renal adrenergic system in vivo. In addition, we were able to demonstrate the existence of a contractile response of Ambystoma vascular smooth muscle to angiotensin II that was blocked by the competitive inhibitor saralasin.

scholarly journals Galectin-7 Impairs Placentation and Causes Preeclampsia Features in Mice

Hypertension ◽  
2020 ◽  
Vol 76 (4) ◽  
pp. 1185-1194 ◽  
Author(s):  
Ellen Menkhorst ◽  
Wei Zhou ◽  
Leilani L. Santos ◽  
Sarah Delforce ◽  
Teresa So ◽  
...  
Keyword(s):  
Renin Angiotensin System ◽  
First Trimester ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Elevated Systolic Blood Pressure ◽  
System Components ◽  
Pregnant Mice ◽  
New Treatment

Preeclampsia is a serious pregnancy-induced disorder unique to humans. The etiology of preeclampsia is poorly understood; however, poor placental formation is thought causal. Galectin-7 is produced by trophoblast and is elevated in first-trimester serum of women who subsequently develop preeclampsia. We hypothesized that elevated placental galectin-7 may be causative of preeclampsia. Here, we demonstrated increased galectin-7 production in chorionic villous samples from women who subsequently develop preterm preeclampsia compared with uncomplicated pregnancies. In vitro, galectin-7 impaired human first-trimester trophoblast outgrowth, increased placental production of the antiangiogenic sFlt-1 splice variant, sFlt-1-e15a , and reduced placental production and secretion of ADAM12 (a disintegrin and metalloproteinase12) and angiotensinogen. In vivo, galectin-7 administration (E8–E12) to pregnant mice caused elevated systolic blood pressure, albuminuria, impaired placentation (reduced labyrinth vascular branching, impaired decidual spiral artery remodeling, and a proinflammatory placental state demonstrated by elevated IL1β, IL6 and reduced IL10), and dysregulated expression of renin-angiotensin system components in the placenta, decidua, and kidney, including angiotensinogen, prorenin, and the angiotensin II type 1 receptor. Collectively, this study demonstrates that elevated galectin-7 during placental formation contributes to abnormal placentation and suggests that it leads to the development of preeclampsia via altering placental production of sFlt-1 and renin-angiotensin system components. Targeting galectin-7 may be a new treatment option for preeclampsia.

scholarly journals Evaluation of the neuroprotective effect of taurine in Alzheimer’s disease using functional molecular imaging

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Se Jong Oh ◽  
Hae-June Lee ◽  
Ye Ji Jeong ◽  
Kyung Rok Nam ◽  
Kyung Jun Kang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Imaging ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Neuroprotective Effect ◽  
Treatment Options ◽  
Brain Uptake ◽  
Positron Emission ◽  
Taurine Treatment

Abstract Alzheimer’s disease (AD) is a chronic neurodegenerative disorder and the leading cause of dementia, but therapeutic treatment options are limited. Taurine has been reported to have neuroprotective properties against dementia, including AD. The present study aimed to investigate the treatment effect of taurine in AD mice by functional molecular imaging. To elucidate glutamate alterations by taurine, taurine was administered to 5xFAD transgenic mice from 2 months of age, known to apear amyloid deposition. Then, we performed glutamate positron emission tomography (PET) imaging studies for three groups (wild-type, AD, and taurine-treated AD, n = 5 in each group). As a result, brain uptake in the taurine-treated AD group was 31–40% higher than that in the AD group (cortex: 40%, p < 0.05; striatum: 32%, p < 0.01; hippocampus: 36%, p < 0.01; thalamus: 31%, p > 0.05) and 3–14% lower than that in the WT group (cortex: 10%, p > 0.05; striatum: 15%, p > 0.05; hippocampus: 14%, p > 0.05; thalamus: 3%, p > 0.05). However, we did not observe differences in Aβ pathology between the taurine-treated AD and AD groups in immunohistochemistry experiments. Our results reveal that although taurine treatment did not completely recover the glutamate system, it significantly increased metabolic glutamate receptor type 5 brain uptake. Therefore, taurine has therapeutic potential against AD.

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